Sick Papes

Limits to sustained energy intake. XVIII. Energy intake and...

butthill — Tue, 04 Jun 2013 09:48:00 -0400

Limits to sustained energy intake. XVIII. Energy intake and reproductive output during lactation in Swiss mice raising small litters.
Zhao ZJ, Song DG, Su ZC, Wei WB, Liu XB, & Speakman JR (2013).
The Journal of experimental biology, 216 (Pt 12), 2349-58 PMID: 23720804

Although binging is often attributed to weak human character, a substantial binge can also help a man get in touch with his/her reckless animal roots. Whether it involves a steaming heap of elk intestines or 3 seasons of Arrested Development, there are some treats that evolution has wired animals to consume beyond the point of reasonable satiety. Giving in to these deep urges is one of the many so-called flaws that the Catholic Church utterly failed to eradicate from our animal constitution.

A recent binge was triggered by the current issue of The Journal of Experimental Biology, which contained no less than IV sick papes about mouse lactation from Dr. John Speakman and colleagues. Further research revealed that, over the past decade, Speakman’s lab has published XVIII papers on this subject, each possessing the formulaic title: Limits to sustained energy intake., etc. This linear corpus of papes is ideally suited to sautéing an entire day in thick fatty mouse milk.

Each of these papes poses the same basic question: which factors determine an animal’s physiological limits? Speakman and colleagues study this question in lactating mice, who expend a massive amount of energy to produce milk for their thirsty pups. Two initial proposals were that milk production is limited by (I) the ability of the gut to digest food or (II) the efficiency of the mammary gland itself.

Through the first X papes in the series, Speakman and his jolly giants tested these hypotheses, as well as a couple other clever theories they dreamed up. My favorite among this back-catalogue is the evocatively titled: Limits to sustained energy intake. X. Effects of fur removal on reproductive performance in laboratory mice.

In this pape, the authors test the hypothesis that energy intake is limited by the capacity of an animal to dissipate heat. They increased the ability of lactating female mice to dissipate heat by shaving them bald as porpoises. Shaved mice ate more heartily and produced more milk, which in turn increased the size of their adorable mouse children. This result contradicted the long-held views that nursing performance is limited by the efficiency of the mother mouse’s digestion and subsequent milk production.

Although these initial results suggested that there might be one or a couple limitations to energy expenditure, the most recent papes (XIV - XVIII) show that the story is actually much more complicated. Under different environmental conditions, lactation efficiency and offspring growth are limited by several overlapping factors. There are also important differences across mouse strains. Despite the lack of simplicity in the underlying biology, the narrative organization of these XVIII papes that ask the same, seemingly basic, question, demonstrate an experimental doggedness that you got to respect.

Brenner, S., Jacob, F., and Meselson, M. 1961. An unstable...

benewencampen — Tue, 21 May 2013 17:38:00 -0400

Brenner, S., Jacob, F., and Meselson, M. 1961. An unstable intermediate carrying information from genes to ribosomes for protein synthesis. Nature (4776): 576-581. [PDF]

Francois Jacob, our hero many times over, died on April 19, 2013. Much has been written about Jacob, including the most inspiring book of all time, his own incredibly-titled autobiography, and many simply jaw-dropping remembrances of his life and career (which didn’t even begin until the age of 30, prior to which point he was fighting against the Nazis as a military doctor). In light of this, we wish to pay our humble respects to Jacob by focusing in on one of his most truly moving papes, in which he helps figure out that mRNA is the intermediate messenger between DNA and protein. As someone who has grown up learning about DNA, RNA and protein from textbooks beginning at the age of 13, it is unspeakably humbling to realize that even such awe-inspiring knowledge as this was unleashed in the form of a single Pape. Given the torrential onslaught of meaningless papes which flood our poor inboxes daily, it is mindboggling to imagine what it must have been like when a pape of this stature and dignity could simply show up in Nature one week. We are all indebted to the True Pape such as this one, and we continue to pray for many more like it. In tribute to Jacob, we heartily recommend you enjoy his wonderful papes first-hand.

By the beginning of the 1960s, it was known that the physical basis of heredity was DNA, and it was strongly believed that the sequence of bases in DNA was co-linear with the sequence of amino acids within proteins. However, it was also known that DNA doesn’t leave the nucleus, whereas protein synthesis takes place in ribosomes, which are in the cytoplasm. The question, therefore, was how does the information get from the nucleus to the cytoplasm, and what is the molecular basis of this process? The best guess at the time was that each ribosome acted as a specialized template for a specific protein. Given that ribosomes are made of RNA, after all, it made perfect sense to imagine that the ribosomal RNA contained sequence-specific information which could encode a specific protein.

[At this point, as an aside, and just out of curiosity, would any of you know how to prove that mRNA is the messenger, even knowing the right answer beforehand? Even if you could go Back to the Future 2 with the book of correct answers to biology, could you figure out how to do these experiments to prove it? I sure couldn’t. There are those who believe that science progresses largely within social constraints, and that the intellectual contributions of specific individuals should not be hero-worshipped, and that somebody else would have figured it out pretty soon anyway. This may or may not be the case (it isn’t - you should definitely hero-worship Jacob and his crew), but I dare you to let this pape wash over your brain and not “need a minute” to collect yourself].

In any case, there is a true story where Jacob visits Brenner and Crick, and he’s telling them about his latest results implying the existence a short-lived molecule between DNA and protein, and they’re all at a party (probably much like the exact opposite of the moon-tower kegger in Dazed and Confused), then someone recalls a recent pape showing that after a virus infects a cell, there is this short-lived species of RNA that arises, which the authors hadn’t known how to interpret in their own pape, and then apparently everybody at the party starts screaming and Jacob doesn’t really speak English but picks it up quickly enough, and later that night they have all of the experiments planned out, and within weeks and they’re headed to Matt Meselson’s lab to use his ultracentrifuge.

The basic set-up is this: grow a bunch of bacteria in heavy nitrogen and carbon, infect them with the virus, and then transfer them immediately to a light medium. Any new products will be light, and any old products will be heavy, and the two can be separated by density in an ultracentrifuge in a cesium chloride density gradient (ground-truthed in Figs. 2 and 3). Using this set-up, they show that upon infection with virus, a new species of RNA is formed (Fig 4), which has a short half-life on the order of 16 minutes (Fig 5), and which associates with the old, heavy ribosomes (Fig 6). That is, the new RNA does not make new ribosomes, but represents a new, previously unknown species of RNA (the messenger!). They then show, using labeled sulfur, that the newly synthesized viral proteins, together with the new RNA, are also found on the old, heavy ribosomes (Figs. 7 and 8), disproving the idea that specialized ribosomes form each protein individually. Hallelujah!

In addition to figuring out one of the basic truths of life, there are two details of this pape which are particularly insane. (1) These experiments, with the exception of the sulfur stuff, were done by Brenner and Jacob in a period of four weeks, in a dirty basement, while visiting a lab that neither Jacob nor Brenner typically worked in. What’s more, the experiments completely failed for the first three weeks and the actual data was gotten in that one final week when no one believed in them. (2) The heavy carbon, which was necessary to separate out old and new ribosomes, was not just something you could buy. According to this great interview with Meselson, it did not exist anywhere in the USA or Japan, and so he got Linus Pauling to directly ask the head of the Soviet Academy of Sciences to make one gram of it for them, which they did by thermal diffusion, over the course of one full year. They delivered it to Meselson as a gas, which Meselson then turned into carbon dioxide that he fed to algae, which photosynthesized the heavy carbon into their bodies, which he then fed to yeast, which he then used to make yeast broth to feed the E. coli. Point is, these people were not kidding around at all, and we are eternally grateful for that.

SICK PAPES SPECIAL ON CONTROVERSY: PART 2 Curr Biol. 2010 Sep...

butthill — Wed, 24 Apr 2013 08:42:00 -0400

SICK PAPES SPECIAL ON CONTROVERSY: PART 2

Curr Biol. 2010 Sep 14;20(17):1534-8.
The role of the magnetite-based receptors in the beak in pigeon homing.
Wiltschko R, Schiffner I, Fuhrmann P, Wiltschko W.

VERSUS

Nature. 2009 Oct 29;461(7268):1274-7.
Visual but not trigeminal mediation of magnetic compass information in a migratory bird.
Zapka M, Heyers D, Hein CM, Engels S, Schneider NL, Hans J, Weiler S, Dreyer D, Kishkinev D, Wild JM, Mouritsen H.

AND

Nature. 2012 Apr 11;484(7394):367-70.
Clusters of iron-rich cells in the upper beak of pigeons are macrophages not magnetosensitive neurons.
Treiber CD, Salzer MC, Riegler J, Edelman N, Sugar C, Breuss M, Pichler P, Cadiou H, Saunders M, Lythgoe M, Shaw J, Keays DA.

There are some scientific subjects that attract recreational bedlamites like seagulls to a coastal landfill. My favorite of these is magnetoreception: the ability of an animal to perceive an ambient magnetic field. Lots of animals can do this—birds, insects, reptiles— and some of them use the earth’s weak magnetic asymmetry to achieve extraordinary feats of navigation. For example, scientific hero Ken Lohmann has shown that sea turtles navigate thousands of miles through the horrific salty ocean in order to meet their half-shelled-brethren at a specific location for an annual Bacchanalian picnic. Ken’s lab also found that if you move a spiny lobster 20 miles in any direction from its preferred hangout spot, it immediately returns directly to its headquarters using cues from the earth’s magnetic field. These and bajillions of other examples demonstrate that many of the earth’s macro-biotic inhabitants can use a magnetic sense to cruise around in magnificent style, which, in my humble opinion, is absolutely fucking fantastic.

Returning to the bedlamites. There are two dudes in particular that illustrate the fact that magnets exert a certain ineffable force upon the zanier castes of our super-organismic civilization. The first of these is shown in the video above: Mr. Harry Magnet, whose extensive pape on personal perception of magnetic fields cannot be deemed sick or otherwise, because it has not undergone rigorous peer review (but we welcome submissions).

The second example comes from Alane Jackson, the purveyor of a theory called magnetrition, which was first explained to me by a youth soccer referee who lived in a wigwam on an magnetically neutral island in the middle of an Alaskan lake. Basically, Alane’s idea is that mitochondria are magnetically charged, and that jostling our cells around causes cytoplasmic stirring, thereby promoting health. I also recommend another section of Alane’s website, titled Smoking is good.

Buried beneath all of this absolutely essential HTML is an equally intense scientific debate about the mechanisms by which real animals measure magnetic fields. So far, two basic mechanisms have been proposed:

(1) MAGNETITE. The magnetite hypothesis was inspired by the observation that some magnet-loving bacteria produce magnetite (Fe₃O₄) crystals that cause them to align with and cruise along the local magnetic vibe. Because magnetite has also been found in the snouts/beaks of fish and birds, it was suggested that the rotation of these crystals could be detected by mechanosensory neurons in the brain. Smaller, “superparamagnetic crystals” have also been found in bird beaks. These crystals do not have a permanent magnetic moment, and therefore do not individually rotate to align with the earth’s magnetic field. However, large arrays of these superparamagnetic crystals would attract and repulse each other under different magnetic field conditions, generating forces that could, in principle, be sensed by neurons.

(2) CRYPTOCHROME. This second mechanism is even bonkers-er. Some radical-pair chemical reactions can be influenced by magnetic forces—one example is the absorption of light by retinal photopigments called cryptochromes. The idea is that the ambient magnetic field would alter the rate of cryptochrome photo-isomerization, so that if a bird were gazing upward at a clear blue sky, it could actually “see” a hazy magnetic field image layered on top of the normal visual scene.

The argument surrounding these two mechanisms is best exemplified in the bird magnetoreception literature, which has been enriched in recent years by a flurry of combative pape-slinging. In one camp, (1) the Wiltschkos and their pals claim that birds use little magnetite particles in their beaks to detect magnetic fields, while in another camp (2) Henrik Mouritsen and his pals claim that magnetoreception arises in the retina, mostly likely through cyptochrome. (3) David Anthony Keays and his buds weighed in on side 2 of the fracas last year, when they suggested that those magnetite particles in the beak are located inside little pieces of biological irrelevance called macrophages.

Although the field of magnetoreception is confusing and controversial, one cannot help but delight in the titillation-level of the questions and the unfettered academic shit-hurling. Magnetoreception is clearly the modern El Dorado, attracting both well-funded academics and itinerant kooks. There is the important possibility that everybody is right— that birds have two independent magnetic senses and so do people, and the booty will be split evenly amongst the Professors and the online gurus. It seems much more likely to me, however, that this entire field is booby-trapped, and that all the magnet-lovers will end up stalking monkeys on a raft as the river below their feet slowly transforms into a cauldron of boiling soup.

SICK PAPES SPECIAL ON CONTROVERSY: PART 1 Hödl, M., &...

benewencampen — Wed, 17 Apr 2013 21:50:00 -0400

SICK PAPES SPECIAL ON CONTROVERSY: PART 1

Hödl, M., & Basler, K. (2012). Transcription in the absence of histone H3.2 and H3K4 methylation. Current biology : CB, 22(23), 2253–2257. doi:10.1016/j.cub.2012.10.008

VERSUS

Pengelly, A. R., Copur, Ö., Jäckle, H., Herzig, A., & Müller, J. (2013). A histone mutant reproduces the phenotype caused by loss of histone-modifying factor Polycomb. Science (New York, NY), 339(6120), 698–699. doi:10.1126/science.1231382

Biology is bursting at the seams with controversy. By far the most important controversy in modern biology is whether taking steroids makes your penis smaller, or whether this is just some D.A.R.E. bullshit they told us as kids to prevent us from fully achieving the glorious manifestation of our god-granted, muscly-man physiques. For those of us who believe that, in fact, steroids may help the enlarge the penis, a sub-controversy exists over whether one should inject the steroids directly into his or her penis. (Answer: currently up for debate on numerous message-boards.) Our colleagues have recently dubbed this expanding field “Penomics,” and we believe it to be rife with promise.

Arguably the SECOND-most important controversy in modern science is related to the importance of histone modifications in gene regulation and epigenetic inheritance. Here’s the low-down: DNA is a linear molecule, but is physically wrapped around structures made of histone proteins (the entire group of histones is collectively known as a “nucleosome”). The histone proteins can be modified at specific amino acids by the addition or removal of chemical groups such as methyl-, or acetyl-, which may help them physically move so that a given piece of DNA is “unwrapped” from the nucleosome and becomes relatively available for transcription.

While there is undoubtedly a strong correlation between histone modification and transcriptional activity, skeptics have pointed out that there remains very little definitive proof that histone modifications are causally important for the regulation of the nearby DNA (i.e. whether a gene is “turned on” or not is influenced by the modifications on the nearby histones). Despite this uncertainty, many writers have gone way overboard and claimed that histone modifications represent the ultimate secret key by which gene regulation is maintained across multiple generations. The masturbatory frenzy of celebration around this field has recently been strongly criticized by the God-like Mark Ptashne in a blunt letter he wrote to the Proceedings of the National Academy of Sciences.

The reason that there is so little direct evidence for the function of histone modification function is because histone proteins are exceedingly difficult to alter in vivo. This is because there are 23 copies of the histone genes (in fruit flies). What are you crazy sons-of-bitches gonna do, mutate ALL of them at once? In fact, yes. Some ambitious lads and lasses took advantage of the fact that these 23 histone genes all lie physically next to each other on the chromosome, and they built a fly with a large chromosomal deletion spanning this entire region. Then, by adding in mutant histone proteins (which, for example, cannot be chemically modified at a specific amino acid), they can ask whether this specific amino acid modification is actually necessary for the histone function.

These two papes present very similar experiments, but report essentially opposite conclusions (sort of). In Pape 1, dudes make a fly whose entire complement of Histone3 cannot be methylated at Lysine #4 (which has been proposed to be required for active transcription at a given genomic site) - i.e. every single nucleosome along the entire genome of a given cell contains histone3 that can’t be methylated at this position at all - and yet they find that these cells can transcribe perfectly fine, and express all the right genes. In other words, methylation at H3K4 cannot be causally required for transcription. Ooh chi wally wally!

But then Pape 2 (Pig in the City) chimes in with a very similar fly, but whose Histone3 cannot be methylated at lysine #27 (another site proposed to be essential, this time for repressing genes). In these motherfucking flies, the cells have completely screwed up gene expression, exactly mimicking the effect of removing the methyl transferase that adds that methyl group. Ooh chi bang bang!!

The debate rages, dudes are battening down the hatches, and our blood-soaked tax dollars continue to fuel this Amazing Race. Me personally, if I have to take sides, I bet that histone modifications are causally important, but this feeling is entirely uninformed, its just my personality!!!

Jakobsen, L., Ratcliffe, J. M. and Surlykke, A. (2013)....

logen1alx — Tue, 19 Mar 2013 15:41:00 -0400

Jakobsen, L., Ratcliffe, J. M. and Surlykke, A. (2013). Convergent acoustic field of view in echolocating bats. Nature. 493, 93-96.

Bats have surpassed all other some odd 6000 species of mammals by evolving the ability to fly. Bats use powered flight to streak through the night, unlike those wanna-be “flying” squirrels, sugar gliders and Brazilian daredevils. In addition to the unique ability to fly, microbats use sonar to “see” delicious insects whilst flapping about (versus the megabats aka flying foxes that presumably use vision to target juicy fruits). Microbats, although micro, come in a range of sizes (~4-16 cm, some would say). The size of a bat relates to the peak frequency of an emitted sonar beam, so that smaller bats use high frequency sonar beams and larger bats use lower frequency sonar beams. For years, bat fanatics have explained this frequency-size relationship under a dubious assumption. The story goes that, because small bats eat small insects, they need higher frequencies (shorter wavelengths) in their sonar beams to adequately reflect off the smaller prey, and vice versa for larger bats. As explained in this most exquisite batpape, this story is a damned lie!

First, even small insects will reflect echoes in the lower end of the bat’s call range. Second, by rudely removing hard-caught meals from bat stomachs, most bats are found to have eaten insects with lengths much shorter than the wavelengths in their sonar beams. To get to the bottom of this bat quandary, these ill authors used a microphone array to measure the shape of the sonar beams emitted by several different species, covering a range of bat sizes, while flying in the same flight arena. They found that each bat species could adjust the shape of the sonar beam dynamically to be wide (encompassing a large volume around the bat) or narrow (encompassing a smaller, more focused region in front of the bat). Narrow sonar beams concentrate energy, which counteracts atmospheric attenuation of high frequency sound, thereby increasing range. Wider beams are better for detecting peripheral targets at shorter ranges. In fact, each species studied used the same sonar beam shape in the fixed experimental arena, predicting that these bats were optimizing their calls to suit the environment that they were placed in.

But how does a gruesome bat change the shape of its sonar beam? There are some options: (1) the frequency of the call can be adjusted, with higher frequencies producing narrower beams than lower frequencies, and (2) the width of the mouth (gape) during a call can be adjusted, with larger gapes producing narrower beams than smaller gapes. Smaller bats have smaller mouths and cannot open as wide as their larger brethren. Smaller bats also cannot fly as fast as big bats in the open field. If you’re a fast flying bat, longer detection ranges are needed to avoid slamming into a tree or a windmill. For big bats, longer ranges are easily obtained by using lower frequency calls, which are more resilient to atmospheric attenuation, and their massive gapes can keep the beam narrow and focused. Small bats don’t have the big-mouth option; instead they must use higher frequencies to narrow the sonar beam, which explains the tendency for small bats to use higher frequency calls. In sum, this wicked batpape brings together an impressive amount of data to show that bats optimize their sonar beam shapes to suit their environments, and provides a vastly improved explanation for the relationship between call frequency and size.

Like the Joker, I am fascinated by this amazing bat technology. How do bats optimize their sonar beams on the fly? Presumably something interesting is going on in those bulging bat brains that allows them to converge on the appropriate beam for every occasion, no matter how big the bat might be.

Ahrens, M. B. and Keller, P. J. (2013) Whole-brain functional...

logen1alx — Mon, 18 Mar 2013 22:46:00 -0400

Ahrens, M. B. and Keller, P. J. (2013) Whole-brain functional imaging at cellular resolution using light-sheet microscopy. Nature Methods.

BAM, aka “Brain Activity Map”, is the brainchild of a Mr. President Obama and colleagues (2013). First announced via the nytimes.com, and first coined by the eminent chef Emeril Lagasse, the BAM seeks, by my understanding, to record the activity of every single neuron in the brain with high temporal and single neuron resolution. Clearly, this is a good idea and everyone should contribute. Some of us (this sickest ones) have contributed more than others (the healthy people). As evidence, gaze upon these fucking splendid videos. Ahrens and Keller used new imaging and genetic methods to BAM the zebrafish larva. Zebrafish have crazy behaviors and have many of the same brain parts that humans do. Now, if you are not satisfied, then read the nature news yourself!

I wrote something about the Brain Activity Map project for RealClearScience. It mostly builds on my...

yelzebub — Wed, 13 Mar 2013 09:44:12 -0400

I wrote something about the Brain Activity Map project for RealClearScience. It mostly builds on my initial feelings about this whole thing.

Beadle, GW and Ephrussi, B. 1936. The differentiation of eye...

benewencampen — Mon, 11 Mar 2013 23:06:00 -0400

Beadle, GW and Ephrussi, B. 1936. The differentiation of eye pigments in Drosophila as studied by transplanation. Genetics 21(4) 225-247.

Beadle & Tatum are basically the Cheech & Chong of biology, in that they are complete geniuses who were way ahead of their time. These were the two heroes who showed up in the 1940s when everyone was wildly speculating about the physical nature of these mysterious things called “genes” and showed that each gene gives rise to one single protein product (the so-called “one gene - one enzyme” hypothesis). Their famous experiments were done by inducing x-ray mutations in a fungus called Neurospora, and then showing that each individual mutation could be rescued by supplying a single, specific nutrient - in other words, that a single genetic mutation causes a single, specific fuck-up in a single enzyme. They even went the extra step of confirming that each of these mutations is inherited like a Mendellian recessive and was therefore a single gene.

The spine-tingling thing about the Beadle and Tatum experiments, though, is that they are so outrageously perfect and beautiful that it is truly terrifying to anyone who has ever tried to do an experiment one’s self. When I read the first Beadle and Tatum pape, it makes me feel like I’m a particularly stupid and tone-deaf 6-year old banging on some pots and pans, hearing the congo playing on “Life’s a Gas” for the first time - i.e. that it is time to throw in the towel because I’ll never achieve anything even approaching that level of perfection.

But buddy, if you are lucky enough (and have access to enough adderall) to have read Beadle’s Noble Prize acceptance speech, you will see that the elegance and clarity of his most famous work is largely the result of a set of earlier experiments done with Boris Ephrussi, which themselves are a LOT more like experiments most of us have attempted: insanely technically challenging, time-consuming and labor intensive, and although really suggestive of something potentially important, never really coming anywhere close to actually proving that potentially awesome thing because that goal won’t be attainable for decades.

Beadle and Ephrussi worked together at Caltech, studying the genetic control of eye-color in fruit flies. Fruit flies were already a powerful system for experimental genetics, so many different mutations had been isolated which gave rise to unusual eye-colors. Working with these different mutant lines, Beadle and Ephrussi physically transplanted the eye primordia from these different mutants into host larvae of different genotypes, making three-eyed flies (this was the psychotically difficult technical part). By reciprocally transplanting between these genotypes, they showed that two of the eye-color mutants (cinnabar and vermillion) were “non-autonomous,” meaning that it was the genotype of the host rather than the donor tissue that controlled the eye color.

The next part, though, is where the scary-genius shit happens. When a cinnabar eye is transplanted into a vermillion hosts, the eye remains cinnabar-colored. But when a vermillion eye is put in a cinnabar host, the eye becomes normal colored! Although this typically shouldn’t make sense to anyone who isn’t on Peyote, Beadle and Ephrussi came up with the idea that perhaps vermillion and cinnabar represent mutations in different genes within a single biochemical pathway that ultimately produce eye pigment. In other words, their idea was that the eye color pathway would be: “Precusor Substance -> Vermillion substance -> Cinnabar substance -> Pigment.” where the substances are diffusible throughout the host body, but interpreted locally within organs, and ultimately control eye color. Even when you know the answer it’s still confusing to think clearly about how this works, so it’s really jaw-dropping how these dudes were able to figure it out from scratch, before anybody else in the entire world understood what it might mean.

These experiments and their interpretation are so hot that my computer battery starts smoking every time I open the PDF. It’s like Beadle and Ephrussi stepped into an ancient temple completely brimming with confusing symbols and death-traps, yet were instantly able to shine the laser on the one specific key symbol that opens the trap door to all the gold coins. And its particularly cool to realize that from these really complex reciprocal eye transplantations, Beadle and the boys were already thinking that genes give rise to distinct biochemical entities, and that because of this, he could design the Beadle and Tatum experiments precisely to prove what he already suspected: that each gene encodes one specific product.

the originalest sick pape

yourbodyismytemp-pal — Thu, 07 Mar 2013 11:57:46 -0500

Blackiston DJ, & Levin M (2013). Ectopic eyes outside the...

butthill — Fri, 01 Mar 2013 17:46:35 -0500

Blackiston DJ, & Levin M (2013). Ectopic eyes outside the head in Xenopus tadpoles provide sensory data for light-mediated learning. The Journal of experimental biology, 216 (Pt 6), 1031-40 PMID: 23447666

Our pals in the Department of Futuristic Neuroscience have recently attracted a lot of attention for a whacky pape that demonstrated that one rat could (sort of) learn to detect signals recorded from another rat’s brain. The main finding of this study, that animals connected by electrodes tend not to ignore each other, is fuzzily heartwarming, but ranks close to Feline papillomavirus on the grand scale of illness.

A much more compelling example of the brain’s dynamic ballsiness (i.e., the ability of neural circuits to learn to detect unfamiliar sensory stimuli), is described in a recent exercise in sickness by the duo of Blackiston and Levin. These pre-pubescent-frog-loving maniacs surgically removed the eyeballs of a couple hundred tadpoles, and then transplanted donor eyeballs onto different regions of the tadpole body (fanny, haunch, etc). The donor eyeballs were labeled with a fluorescent protein (RFP), so they could monitor the axons of the transplanted optic nerve. Most of the resettled eyeballs did not successfully innervate the central nervous system, but about ¼ of them managed to connect to the gut, and another ¼ innervated the spinal cord.

Blackiston and Levin then tested the population of chimeric tadpole beasts with an associative learning task that required the tadpoles to detect light in order to avoid an electric shock. A small number of the 200 freak tadpoles could learn to avoid red light, despite the fact that they did not have normal eyes. All of the successful learners had transplanted eyeballs that innervated the spinal cord.

It’s already incredible that transplanted eyeballs can successfully wire up to the spinal cord; the fact that tadpoles can then use the whimsical retina/spinal cord circuit in a behavioral task seems, at first glance, to defy the 14^th amendment of biology. But we’ve known for a long time that the nervous system is able to adapt to novel inputs. For example, the visual cortex of blind people can be colonized by auditory and somatosensory inputs, allowing them to fluently read using touch (Braille) and echolocate like bats (??).

The interesting question is not whether animals can learn to detect exogenous signals (e.g., spikes transmitted from a Brazilian rat’s brain), but how the hell the nervous system pulls out such meaningful signals of hope against the noisy background of torrential chaos and despair. This is some boring biology shit. In the meantime let’s get psyched about building an exoskeleton for the World Cup and teaching Big-Dog to throw cinder blocks.

sick papes would like to officially call out those nobel prize winners who only grow their hair out...

yourbodyismytemp-pal — Wed, 13 Feb 2013 22:56:55 -0500

sick papes would like to officially call out those nobel prize winners who only grow their hair out after they got their prize. i’m embarrassed i even have to write this, you poser shits. as if you weren’t already getting enough attention. if we see you in the street we’re apt to de-tail you through the confiscation of your “life is good” scrunchy. get a grip, last warning.

Gene-Swapping Spits Insight into the Mouth of the Vertebrate Mind

yourbodyismytemp-pal — Sat, 09 Feb 2013 16:35:00 -0500

Nithianantharajah et al. 2012. Synaptic scaffold evolution generated components of vertebrate cognitive complexity. Nat Neuro

Ryan et al. 2012. Evolution of GluN2A/B cytoplasmic domains diversified vertebrate synaptic plasticity and behavior. Nat Neuro

Start private browsing. Under my favorite categories of experiments there on the right you’ll find “gene swapping.” Click on that. O sweet gene swapping. I’m back. It’s like momma earth just spat out DNA here just so experimentalists could do gene swap experiments and fucking rub their hands together and snort and drink coffee and wait for the results. I should start explaining gene swap experiments in this sentence but I just need to say one more time: in the world of dazzling complexity that is the cell or (eek) tissue or even (eek eek) the whole enchilada, swapping genetic elements offers a straightforward molecular razor for whatever. Currently we do it one element at a time, but in the future, who knows how many combinations we can apply and track before our brains explode.

Okay a gene swap experiment is pretty much exactly like it sounds. Change a single gene in some subtle or not so subtle way to something else. Make it non-functional say, or maybe just get a mutation that turns the protein in the human form or resistant to a flavor of post-translational modifications or swap subsets of gene-parts to figure out what part of the protein does what. And it’s slick as shit. Cause that baby’s siblings don’t have the change and you just compare your normal dude to the mutant you’re studying. Get at that infinitely complex cool and mysterious result stemming from something very discreet you did on the atomic/nanometer scale. Not bad human experimentalism not bad!

I’m blowing chunks on a couple of back to back Nature Neuroscience boon-diggler gene swap experiments right now: Nithianantharajah et al. and Ryan et al. (2012). I honestly follow this shit dropping from the Grant lab in the UK but I don’t understand it. I mean I understand it. I get their experiments for sure and that they’re trying to use a comparative approach across species to examine the evolution of the synapse and, well, cognition. But as pretty much the only guys in this business, it’s hard to predict what they’re going to pop out next.

Nithianantharajah et al (just fyi, it takes 10 ocean mana to tap this character into play but it’s worth it cause he’s got 12 hit points) assay the cognitive capabilities of mice that lack one of four Dlg genes. The Dlg family constitute major structural components of that sweet little signaling organelle that makes up the receiving half of the excitatory synapse. If the post-synaptic density is a lobster trap, then the Dlgs are the different gauges of chicken wire. There are four of these boogers because of ancient genome duplications in the vertebrate lineage. So to understand how each Dlg contributes to cognition is to understand how the duplication of genes allow each dupli-can’t to involve into a dupli-can!: a twisted sister of it’s own specialized function. One cool thing about this pape is the authors assay the cognitive prowess of each Dlg mutant mouse by forcing them to play an iPad. Like our society, but literally thirsty instead of spiritually thirsty. Each individual Dlg knock out showed different cognitive deficiencies suggesting a lack of functional redundancy in each of the 4 genes. Interestingly, Dlg3 knock out mice showed increased performance in tasks requiring cognitive flexibility and attention, meaning they might have a shot at beating my Mom at bejeweled. The take home load is that in these knock-out swap experiments, the authors demonstrate that ancient genome duplications allowed for the elaboration of the cognition of mice. That’s a pretty big rip on theory bong. Thanks straightforward knock out experiments and tablet computing!

Ryan et al. swap out the intracellular tails of another set of duplicated synaptic genes. This time the targets are the two main subunits of the NMDA receptors. NMDA receptors are ion channels that serve as coincidence detectors of neuronal activity and flux calcium, in what is equivalent of a particular synapse sending a text message about it’s state (“party’s on/party sux”) to it’s nearest neighbors and in some cases the friggin nucleus. The tails of the two subunits are a particularly informed switch since these parts of the proteins are the most divergent and function to bind different swaths of intra-cellular molecules. So it would seem each tail recruits a different signaling network to respond to calcium. So how do we test how this tail divergence influences cognition? GENE SWAP and iPADS baby!

So keep in mind: swapping out the tail of sub-unit A onto B means that both proteins have A tails and no B tail exists. So get double-duty of one tail and a complete lack of duty of the other. So whatever phenotypes emerge from these swappings could be due to a lack of B or over-binding from A (or synergies in between).

These dudes conveniently grouped the behaviors that were insensitive to the swap, only sensitive to unidirectional swaps, or sensitive to both swaps. Only impulsivity related behaviors required having both tails. Perception, anxiety, coordination and general activity levels required having one tail or the other. Learning in general remained intact when tails were swapped. Using the divergent tails of the NMDA receptor tails as a proxy, the authors suggest that more sophisticated regulation of motivational and emotional behaviors was selected for during the early evolution of vertebrates; learning is based on function that is redundant across tails and thus an older phenomenon.

Wow! Duh! And that’s how it goes in the field of synapse evolution

Waters, J., Holbrook, C., Fewell, J., & Harrison, J. (2010). Allometric Scaling of Metabolism,...

jamescrall — Tue, 29 Jan 2013 10:00:00 -0500

Waters, J., Holbrook, C., Fewell, J., & Harrison, J. (2010). Allometric Scaling of Metabolism, Growth, and Activity in Whole Colonies of the Seed‐Harvester Ant Pogonomyrmex californicus The American Naturalist, 176 (4), 501-510 DOI: 10.1086/656266/>

We all know the feeling: You’re lying naked in a sun-soaked field after taking a fistful of mushrooms and watching waves of energy explode through your friends’ braincases. And no matter how long you watch the trees breathe, just can’t shake the question: “Where does my body end and the world begin?” Turns out this cosmic question has a hallowed tradition, and just about no one knows how to draw boundaries around a body.

The little guys that fucks with our best minds most royally on this distinguished issue are the social Hymenoptera (ants, bees, and wasps). Dudes have been flubberbusting long and hard about whether we should think about the bees in a hive (or people in a city, or dicks in a game of dick jenga) as a wonderful communion of separate beings or as all just the dangly bits of one MegaMan. As the disturbing old saying goes, there’s many ways to skin a cat, but what perverted shitbag wants to to skin a cat a bunch of different ways? So the world was on the verge of turning its back forever on this age old question and exploding in a supernova of its own ignorance.

That is until some brave souls (Dr. James Waters and colleagues) figured out the illest of ways to blow the lid off a part of this problem. But let me slow my roll a bit and fill in the rubbly background that makes it crystalline just way this pape is so sick:

For just about forever, we’ve known one thing about bodies for sure: how fast they use up energy (their metabolic rate) has a crazy strong relationship with how big they are. Specifically, bigger things use less energy per unit body mass than small things. So basically, one giant 100 kg rat should be using up energy much slower than 100 puny 1 kg rats, even though the grand total of rat meat is the same in both cases.

So, what these dudes did was investigate this same problem in ants, the superest of superorganisms. In an ant colony, you should be able to predict how much energy the whole colony is using based on their average body mass (e.g. you should be able to just sum up the metabolic rate of a bunch of small ants). But when they put whole colonies of these little guys in a fancy box that measures how fast they’re using up their cosmic energies, turns out they’re doing exactly not that. Specifically, their metabolic rate is what you’d predict for a single organism that had the collective mass of all the ants. And metabolic rate changes with colony size the same way it does for bigger bodies. So, in summary, ants (a) are fucking crazy, and (b) on both the mystical and physical planes appear to be working just like a single, physically integrated body does. Why? Lord knows. But this paper is opening up ways to answer that question and new ways to think about the most basic aspects of how organisms are put together. Sick.

Oh, and ants do this too.

Gymrek M, McGuire AL, Golan D, Halperin E, & Erlich Y...

benewencampen — Tue, 22 Jan 2013 15:54:00 -0500

Gymrek M, McGuire AL, Golan D, Halperin E, & Erlich Y (2013). Identifying personal genomes by surname inference. Science (New York, N.Y.), 339 (6117), 321-4 PMID: 23329047

For most of us, David Golann became a household name when CNN caught him heroically saving the life of a terrified rat stuck in New York City traffic. (“I just sort of know what it’s like to be pretty scared.”) So it was not surprising this week when several thousand fans wrote in to ask if this was the same David Golan who appears as third author on this crotch-kickin’ Pape which burst forth onto the earth-realm last week. To which we reply: thank you for writing, but, no, these two men spell their names differently.

But on the topic of last names, there are now many services that allow folks to try to identify the last name of their biological father via DNA testing. For these sites, you send in some DNA, and they examine sequences on the Y-chromosome (which are inherited only from your father), and then they look for the closest match in their big ol’ sequence databases. While they probably don’t have your father himself in their database, they are likely to have several distant patrilinear relatives, and by analyzing those names, they can hypothesize the likely last name of your father, and apparently with pretty good success.

What the Foot Clan-esque authors of this pape realized is that these publically available databases allow hackers to identify the names of the “anonymous” genomic databases that are increasingly available on the internet. The basic algorithm is: submit the Y-chromosome data from these supposedly anonymous genomes to the paternity websites, which gives you the most likely last names. At this point, you’ve narrowed it down to ~40,000 individuals. Then, parse through these candidates using two other publically available pieces of information (D.O.B. and State of residence), which typically narrows it down to about 12 males. At which point, you are fucked.

Basically, these dudes are like Robert Redford’s gang in Sneakers: they hacked the system not to do harm, but to show us the system’s weakness. I mean, it only works on males and it doesn’t work all the time, but it’s still NASTY!!!

Eliasmith, C., Stewart, T., Choo, X., Bekolay, T., DeWolf, T., Tang, Y., & Rasmussen, D....

istudyvision — Thu, 03 Jan 2013 16:23:00 -0500

Eliasmith, C., Stewart, T., Choo, X., Bekolay, T., DeWolf, T., Tang, Y., & Rasmussen, D. (2012). A Large-Scale Model of the Functioning Brain Science, 338 (6111), 1202-1205 DOI: 10.1126/science.1225266

The H. P. Lovecraft novella At the Mountains of Madness is a story about scientific hubris, and the insignificance of human achievement when confronted with the vastness that is the cosmos. The central characters are scientists searching the Antarctic for novel geological or biological forms. They uncover a world of strange, ancient beings, seemingly preserved in the ice. Their discovery has profound implications for the nature of biological evolution, and perhaps the history — and future — of earth itself. The primary entity they find is a god-like tentacled, winged, gilled monstrosity with strange geometrical features. We are given this account:

“It had digestion and circulation, and eliminated waste matter through the reddish tubes of its starfish-shaped base … The nervous system was so complex and highly developed as to leave [the scientist] aghast. Though excessively primitive and archaic in some responses, the thing had a set of ganglial centers and connectives arguing the very extremes of specialized development. Its five-lobed brain was surprisingly advance and there were signs of a sensory equipment, served in part through the wiry cilia of the head, involving facts alien to any other terrestrial organism … It was partly vegetable, but had three-fourths of the essentials of animal structure.”

I had a similar reaction when reading about S.P.A.U.N., the monstrous creation described by Eliasmith et al. in their pape: “A large-scale model of the functioning brain”. The title alone suggests a new and scary precipice of human achievement. And a most sick pape.

S.P.A.U.N. is half way between a robot and a computer program. It has a small camera attached to its head, and a robotic appendage extending from an implied torso that is capable of drawing all manner of digits between 0 and 9. Its brain has multiple sub-systems that independently control the encoding of visual input, reward, working memory, decoding, and motor output. The thrust of Eliasmith et al.’s pape is not that any one component of S.P.A.U.N. is new, but that it can perform not just one task but a variety of tasks, all of which humans can perform, and that its modular architecture resembles and realistically models at least some aspects of the human brain.

How close does S.P.A.U.N. come to resembling the brain? Each of its systems are meant to correspond to cortical and sub-cortical brain areas or functions, though much of the correspondence seems superficial. For example, S.P.A.U.N. has a system for handling “Visual Input”. It’s implied that it corresponds to areas V1, V2, V4, and IT of the primate visual pathway. But S.P.A.U.N. cannot mimic known processing in all those areas because we still don’t know what they do! The visual system of S.P.A.U.N. also reveals that its individual neurons are not as realistic as you might think. The authors stress that it uses biologically-realistic neurons with neurotransmitter dynamics, but most of the visual system instead uses simple linear combinations and thresholding. It’s hard to evaluate these shortcuts because the system is so complex.

So S.P.A.U.N. can do some cool tricks and kind of maybe looks like a brain. Can it fight a bear in one-on-one combat? Definitely not. S.P.A.U.N.‘s proponents admit that it is not the most impressive robot. When I googled “what is the sweetest robot?” I found this strawberry-picking robot. It uses 3D image processing to evaluate ripeness, and can delicately pluck luscious plump strawberries from their stems. That seems more impressive than S.P.A.U.N.

Becoming the best robot is not S.P.A.U.N.’s goal. What is the goal? Building AI systems that perform complex, physical, interactive tasks with flexible, modular systems resembling known biology, that could in principle help us understand how brains work. A longstanding, and recently popularized but criticized, tradition in AI is to build systems that have vast representational power, memory, and fancy statistical learning algorithms, but generally produce simple outputs. For example, a computer vision system that encodes a complex image but only needs to decide which of 10 different kinds of objects it is looking at. But most animals evolved to do more than spit out a 10-bit vector. They engage in real-time with a dynamically changing world. S.P.A.U.N.’s complex motor output and working memory is a step forward, but its emphasis on symbolic reasoning — which number comes next in a sequence? — is excessively abstract. If such symbolic reasoning evolved as an abstraction of more directly-physically-realized functions — when can I jump to make sure I catch the next mouse? — why not first try to build robots that can accomplish those tasks? I recommend the exciting research program of the “embodied robotocist” Rodney Brooks, especially his efforts in the 1990s to build robots with distributed control systems for path finding and navigation. He also appears, looking entirely crazed, in this movie, which features robots, lion taming, tree grooming, and naked mole rats. We are truly standing beneath the Mountains of Madness.

By popular demand, Sick Papes now offers Exclusive shirts and...

benewencampen — Wed, 02 Jan 2013 19:30:00 -0500

By popular demand, Sick Papes now offers Exclusive shirts and reflective safety work vests for all our beautiful fans out there!!

http://sickpapes.spreadshirt.com/

Gilbert, S., & Zevit, Z. (2001). Congenital human baculum...

benewencampen — Wed, 19 Dec 2012 22:11:00 -0500

Gilbert, S., & Zevit, Z. (2001). Congenital human baculum deficiency: The generative bone of Genesis 2:21-23 American Journal of Medical Genetics, 101 (3), 284-285 DOI: 10.1002/ajmg.1387

Humans are the only primates that don’t have bones in their penises (dicks). This beautiful pape, reproduced in full above, proves that this is because God took the penis bone out of Adam to make Eve.

Though hilarious, this pape is actually a work of legit biblical scholarship by my scientific hero, Dr. Scott Gilbert, who literally wrote the book on Developmental Biology, and is the best teacher on the planet. Congratulations on your retirement, Dr. Gilbert!

Krieger J, Grandy R, Drew MM, Erland S, Stensmyr MC, Harzsch S,...

butthill — Tue, 18 Dec 2012 19:11:00 -0500

Krieger J, Grandy R, Drew MM, Erland S, Stensmyr MC, Harzsch S, & Hansson BS (2012). Giant Robber Crabs Monitored from Space: GPS-Based Telemetric Studies on Christmas Island (Indian Ocean). PloS one, 7 (11) PMID: 23166774

Anybody who knows me will tell you that I have a soft spot in my heart for the hard shell of our fellow crab-man. For all the land-lubbers out there, the crab is a heavily-armored, sideways-running little fellow that specializes in shoveling detritus (= trash) into its adorable little mouth with an often over-sized claw appendage. To me, the main appeal of the crab is its dignified air of feistiness. Unlike most softy animals, crabs do not like to be handled, and if you pick them up they will pinch you with all the hatred they can muster. Crabs also have beautiful brains and, as we shall see, possess a unique brand of crusty intelligence.

There are all sorts of freaky crabs out there, but the most inspiring is the absurdly proportioned giant robber crab that resides on Christmas Island in the South Pacific. These friggin crabs can weigh about 10 lbs, they climb trees, and they rip apart coconuts and devour them like their mike’s and ike’s (sic). This cushy crab lifestyle allows them to live to the ripe age of 60. Some folks in the recently prolific Hansson Lab at the Max Planck Institute for Chemical Ecology somehow convinced somebody to let them go to Christmas Island and study the navigational abilities of giant robber crabs. Their experimental protocol went as follows:

Snatch a robber crab
Glue a GPS tracking device to its carapace
Sit back and watch where it goes via satellite transmission
Snatch the crab again, put in a trash bag, transport it across the island, and release it
See if the crab can get back home

This pape clearly demonstrates that robber crabs live a rambling lifestyle. After spending a few days or weeks in one area, a crab will get the itch to roam, and will pick up and haul his barnacled ass from the inland rainforest to the seashore. After a spell at the shore, he’ll pack up and hitch back into the rainforest. Over time, robber crabs learn preferred routes that they repeatedly traverse throughout their long lives. Most remarkably, if you put a crab in a trash bag and haul it a mile away, it will almost immediately return to the spot where you snatched it.

Aside from the obvious conclusion that robber crabs are dynamic, intelligent beasts, this pape also establishes the robber crab as an important model system for studying what it means to live a deeply fulfilling life.

Schwager, E., Pechmann, M., Feitosa, N., McGregor, A., &...

benewencampen — Sat, 08 Dec 2012 16:40:00 -0500

Schwager, E., Pechmann, M., Feitosa, N., McGregor, A., & Damen, W. (2009). hunchback Functions as a Segmentation Gene in the Spider Achaearanea tepidariorum Current Biology, 19 (16), 1333-1340 DOI: 10.1016/j.cub.2009.06.061

and

Khadjeh, S. et al. Divergent role of the Hox gene Antennapedia in spiders is responsible for the convergent evolution of abdominal limb repression. Proc Natl Acad Sci USA 109, 4921–4926 (2012).

Even in my wildest imagination, I could not have dreamed up out of a stupider fucking abstract than this one, where two halfwit cretins claim that there may be a single gene associated with credit card debt. I will give you a moment to let the infurating constellation of ahistorical classism and racism sink in (did you also find the gene for not having health insurance? for working three jobs?), while I practice my deep breathing exercises, chief a one-hitter to my dome, and prepare my loving thoughts on two ACTUALLY MEANINGFUL studies on the astounding effects of single genes. Namaste, true researchers of the embryological process.

Now then. Although I cannot mask my disappointment that it has taken 2012 years, I am nonetheless ecstatic to report that humankind has collectively figured out how to make four-legged spiders (Pape 1, see video) and ten-legged spiders (Pape 2). And the crazy thing is that in both cases, these massive changes are the result of removing a single gene from the spiders. Of course, these single genes encode for those powerful regulatory proteins that act very early in development to organize the collective activities of hundreds of other genes later on to generate large portions of the body.

For more information on the actual, non-intuitive relationship between genes and biological reality, I encourage you all to read up on my favorite experiments ever done.

Druckmann, S., & Chklovskii, D. (2012). Neuronal Circuits...

butthill — Tue, 04 Dec 2012 13:45:00 -0500

Druckmann, S., & Chklovskii, D. (2012). Neuronal Circuits Underlying Persistent Representations Despite Time Varying Activity. Current Biology, 22 (22), 2095-2103 DOI: 10.1016/j.cub.2012.08.058

To celebrate the dawn of December, a month of intense introspection and widespread brooding, Sick Papes brings you an exclusive soul-wrenching interview with neuroscientist and celebrity theoretician, Dr. Shaul Druckmann. Shaul’s recent pape (w/ Mitya Chklovskii) suggests a fresh answer to a beguiling question- how does the brain maintain persistent representations despite the fact that neuronal activity is constantly changing?

Personal experience tells us that the brain can maintain stable representations of images, numbers, and ideas for seconds and minutes. However, the activity of neurons in brain regions thought to be involved in working memory, such as prefrontal cortex, varies on a much faster time scale, (~10-50 milliseconds). Shaul’s pape proposes a network model, called FEVER, which can maintain persistent representations even as the activity of individual neurons varies. It turns out that this network model has many features in common with the organization of real cortical networks.

SP: If I’ve got my mules in order, your model network is constructed such that the receptive field of each neuron is equivalent to a weighted sum of the receptive fields of all other neurons in the network, and the weights in this weighted sum are the strength of synaptic connections between neurons. This allows the activity of individual neurons to vary, while the output of the network remains constant. This structure seems precarious. If I were to go into your brain and cut one single synaptic connection, how would this affect stable representations in a dense FEVER network? In other words, how robust is this network to wanton destruction?

SD: Yup, your mules are definitely in order and marching. As you say, destroying synaptic connections will momentarily throw the network off balance. However, since the representation is highly overlapping and there are many ways to represent each stimulus there would be no problem readjusting the network so as to ignore the destroyed part of the network. Given the high degree of overcompleteness that we suspect exists in cortex, there is a lot of room to recover from damage.

SP: In his Tractatus, Wittgenstein proposes that, “A logical picture of facts is a thought”; in other words, that thoughts must adhere to the same logical form as things in the real world. Agree or disagree?

SD: Wittgenstein huh? I am not sure I can even properly pronounce his name, much less understand his writings. The end of my serious reading of philosophical literature timeline is more or less with Kant… Regardless, I am not sure I read the sentence the same way you do. “A logical picture of facts is a thought”. First, I like the stress on the term “picture of facts” which for me relates the thought to the many aspects of taking a picture: we select what to put in our frame and what to keep out, the lighting we throw on the objects matters a lot as well as the angle and ultimately it needs to be developed to become a real thing (okay maybe the last one was a stretch). Regarding what thoughts must adhere to, I am not sure thoughts are under control, so lets read “thoughts” as “theories”. I strongly believe that theories must first and foremost have a sound logical structure. In one interpretation that is pretty straightforward since it just means that the math needs to check out. However, I believe that, somewhat related to that sentence, one of the most interesting things about theories is that they rearrange facts that we thought we previously knew into a new order. If that new order makes more “sense” and teaches you (the experts) new things about the facts then the theory is actually valuable. Anyhow, this sounds like something better talked about over a beer…

SP: Your pape addresses how a brain might hold onto specific representations for periods of seconds, even as the activity of individual neurons varies wildly during this period. A slightly different problem is how human thought and perception seems to occur on the time-scale of seconds, despite the fact that neural activity varies on the order of milliseconds. Do you think this is simply a matter of perception, or do evolving network dynamics across longer time scales matter?

SD: Actually our first draft discussed that briefly, but reviewers hated it since it was too speculative. I think there are two possibilities, one is that representation is constantly changing, but there is a little leprechaun working really hard in our brain all the time to make sure our conscious perception is smooth (this may sounds crazy, but think change-detection blindness). The other is that the networks themselves bridge the gap between the time scale of neural activity (milliseconds) and the time scale of the world (seconds say) by mechanisms such as the one we describe in order to allow downstream circuits a smooth readout of the representation and the leprechaun to have a much more relaxed life. Which is true? I really don’t know.

SP: When you are building a model, do you start with the acronym first and work backward? Or do you build the model first and then tweak it until it fits with a catchy acronym?

SD: Given the allowed artistic freedom of basically picking any random word and letter within it for an acronym it is pretty easy to find one once the work is done. But what you suggests sounds fun, randomly thinking up an acronym, finding the most reasonable sentence you can attach to it and seeing whether that inspires and idea worth working through.

SP: Do you think the phrase “persistent representation” accurately describes what is happening in the brain during working memory? For example, remembering a phone number requires a certain amount of active rehearsal, and is susceptible to distraction. Why must prefrontal cortex maintain a representation within itself, rather than relying on repeated structured inputs from other sensory networks?

SD: In the delayed-match-to-sample working memory task design as much as possible is done to eliminate the possibility of input driven memory (turning stimulus on only transiently, long delay periods). Therefore, that is less of an option in my opinion. More generally though, if it is an input driven memory then one has to answer the question how does whatever circuit that provides the input keep its ability to provide an input for such a long time despite the transient stimulus. Then all our explanations would need to be shifted to that area. I don’t think it has been worked out in an airtight manner that this isn’t a possibility, but I think it is less likely.

SP: In Borges’ story, ”Funes the Memorious”, a young boy falls off a horse and loses his ability to forget. His life is haunted by the banal details of every moment he has ever experienced, including all the associated physical and emotional sensations. Are there certain conditions under which a FEVER network architecture could result in such a condition?

SD: Good point! In fact the way we develop the math in the first section leads to a network with an infinite integration, which is exactly Borges’ idea, sans the horse. That’s why we later add the scaling factor to the equation that allows you to have a very long, but not infinite, time constant. Otherwise, with an infinite time constant one would run into all kinds of problems such as saturation due to the integration of all the (banal) past stimuli ever encountered.

SP: One method to test the relevance of the FEVER network is to compare the synaptic structure of a cortical network to the range of eigenvalues predicted by the model. Are there any unexpected features of the eigenspectrum that you could look for in real cortical networks? You mention a few in the paper that support your model (e.g., prevalence of reciprocal connections), but are there others that would be worth looking for?

SD: In terms of synaptic reconstruction, I think the neat thing to do is to try to map the receptive field of neurons and then do EM reconstruction a la Denk. Then one option is trace down the axon of a single cell, find all the post-synaptic cells, sum up their receptive fields and see if you come up with the original neuron’s own receptive field (I guess you could do it with trans-synaptic viruses in principle too). The tricky part is that you need to know the weight of the connection, which might not be easy/possible from EM (actually everything about that idea is tricky). More generally, I think the most interesting concept to look for is the idea of coding vs. non-coding directions in activity space which our theory suggests. Not all activity patterns were created equal! I believe this has serious implications for how to interpret multi-neuron population recordings and that is something I want to take a closer look at.

SP: What is the sickest pape you have read in the last 2 months?

SD: Sickest pape: ice in Mercury’s north pole. Ice was apparently delivered by comets or asteroids! Surface temperatures of 400 celsius (not in the shade) but alien (to mercury) ice in the deep shade still survived. How cool is that?